Substantially homogeneous aqueous suspensions of low density microspheres are presented as contrast media for imaging the gastrointestinal tract and other body cavities using computed tomography. In one embodiment, the low density microspheres are gas-filled. With computed tomography, the contrast media serve to change the relative density of certain areas within the gastrointestinal tract and other body cavities, and improve the overall diagnostic efficacy of this imaging method.

Patent
   5547656
Priority
Apr 05 1991
Filed
May 24 1995
Issued
Aug 20 1996
Expiry
Aug 20 2013
Assg.orig
Entity
Large
184
44
all paid
43. A substantially homogeneous aqueous suspension of low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon.
22. A contrast medium for diagnostic imaging comprising a substantially homogeneous aqueous suspension of low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon.
58. A kit for diagnostic imaging of a patient comprising low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon, in combination with a thickening or suspending agent.
1. A contrast medium for computed tomography imaging of the gastrointestinal region or other body cavities comprising a substantially homogeneous aqueous suspension of low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon.
57. A kit for computed tomography imaging of the gastrointestinal region or other body cavities of a patient comprising low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon, in combination with a thickening or suspending agent.
60. A method of providing an image of a region of a patient comprising
(a) administering to the patient a contrast medium comprising a substantially homogeneous aqueous suspension of low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon, and
(b) scanning the patient using diagnostic imaging to obtain visible images of the region of a patient.
62. A method for diagnosing the presence of diseased tissue in a patient comprising
(a) administering to the patient a contrast medium comprising a substantially homogeneous aqueous suspension of low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon, and
(b) scanning the patient using diagnostic imaging to obtain visible images of any diseased tissue in the patient.
59. A method of providing an image of the gastrointestinal region and other body cavities of a patient comprising
(a) administering to the patient a contrast medium comprising a substantially homogeneous aqueous suspension of low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon, and
(b) scanning the patient using computed tomography imaging to obtain visible images of the gastrointestinal region or other body cavities.
61. A method for diagnosing the presence of diseased tissue in the gastrointestinal region or other body cavities of a patient comprising
(a) administering to the patient a contrast medium comprising a substantially homogeneous aqueous suspension of low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon, and
(b) scanning the patient using computed tomography imaging to obtain visible images of any diseased tissue in the patient.
2. A contrast medium according to claim 1 wherein said microspheres comprise synthetic polymers or copolymers prepared from the group of monomers consisting of acrylic acid, methacrylic acid, ethyleneimine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate, lactic acid, glycolic acid, ε-caprolactone, acrolein, cyanoacrylate, bisphenol A, epichlorhydrin, hydroxyalkylacrylates, siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol, hydroxyalkyl-methacrylates, N-substituted acrylamides, N-substituted methacrylamides, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene, p-amino-styrene, p-amino-benzyl-styrene, sodium styrene sulfonate, sodium 2-sulfoxyethyl methacrylate, vinyl pyridine, aminoethyl methacrylates, 2-methacryloyloxy-trimethylammonium chloride, N,N'-methylenebisacrylamide, ethylene glycol dimethacrylates, 2,2'-(p-phenylenedioxy)-diethyl dimethacrylate, divinylbenzene, triallylamine, and methylenebis-(4-phenyl-isocyanate).
3. A contrast medium according to claim 2 wherein said microspheres comprise synthetic polymers or copolymers prepared from the group of monomers consisting of acrylic acid, methacrylic acid, ethyleneimine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate, lactic acid, glycolic acid, ε-caprolactone, acrolein, cyanoacrylate, bisphenol A, epichlorhydrin, hydroxyalkylacrylates, siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol, hydroxyalkyl-methacrylates, N-substituted acrylamides, N-substituted methacrylamides, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene, p-amino-styrene, p-amino-benzyl-styrene, sodium styrene sulfonate, sodium 2-sulfoxyethylmethacrylate, vinyl pyridine, aminoethyl methacrylates, and 2-methacryloyloxy-trimethylammonium chloride.
4. A contrast medium according to claim 1 wherein said microspheres comprise synthetic polymers or copolymers selected from the group consisting of polyacrylic acid, polyethyleneimine, polymethacrylic acid, polymethylmethacrylate, polysiloxane, polydimethylsiloxane, polylactic acid, poly(ε-capro-lactone), epoxy resin, poly(ethylene oxide), poly(ethylene glycol), polyamide, polyvinylidene-polyacrylonitrile, polyvinylidene-polyacrylonitrile-polymethylmethacrylate, and polystyrene-polyacrylonitrile.
5. A contrast medium according to claim 1 wherein said microspheres comprise polyvinylidene-polyacrylonitrile copolymer.
6. A contrast medium according to claim 1 wherein the microspheres are prepared by a heat expansion process.
7. A contrast medium according to claim 1 wherein said microspheres comprise a polyoxypropylene-polyoxyethylene copolymer.
8. A contrast medium according to claim 1 wherein said perfluorocarbon gas is selected from the group consisting of perfluorocarbons having between 1 and about 9 carbon atoms and between about 4 and about 20 fluorine atoms.
9. A contrast medium according to claim 8 wherein said perfluorocarbon gas is selected from the group consisting of perfluorocarbons having less than about 4 carbon atoms and less than about 10 fluorine atoms.
10. A contrast medium according to claim 8 wherein said perfluorocarbon gas is C3 F8.
11. A contrast medium according to claim 8 wherein said perfluorocarbon gas is C4 F10.
12. A contrast medium according to claim 8 wherein said perfluorocarbon gas is C5 F12.
13. A contrast medium according to claim 8 wherein said perfluorocarbon gas is C6 F14.
14. A contrast medium according to claim 1 further comprising a thickening or suspending agent.
15. A contrast medium according to claim 14 wherein said thickening or suspending agent is selected from the group consisting of cellulose, carboxymethylcellulose, methylcellulose, and methylhydroxycellulose.
16. A contrast medium according to claim 15 wherein said thickening or suspending agent is methylcellulose.
17. A contrast medium according to claim 1 further comprising a compound selected from the group antacids, antiflatulents, antifoaming agents, and surfactants.
18. A contrast medium according to claim 17 wherein said compound selected from the group of antacids, antiflatulents, antifoaming agents, and surfactants, comprises a polymeric siloxane.
19. A contrast medium according to claim 18 wherein said polymeric siloxane is dimethylpolysiloxane.
20. A contrast medium according to claim 19 wherein said dimethylpolysiloxane is simethicone.
21. A contrast medium according to claim 1 wherein said microspheres comprise a polyoxypropylene-polyoxyethylene copolymer, and said perfluorocarbon gas comprises C5 F12, and wherein said contrast medium further comprises methylcellulose and simethicone.
23. A contrast medium according to claim 22 wherein said microspheres comprise synthetic polymers or copolymers prepared from the group of monomers consisting of acrylic acid, methacrylic acid, ethyleneimine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate, lactic acid, glycolic acid, ε-caprolactone, acrolein, cyanoacrylate, bisphenol A, epichlorhydrin, hydroxyalkylacrylates, siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol, hydroxyalkyl-methacrylates, N-substituted acrylamides, N-substituted methacrylamides, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene, p-amino-styrene, p-amino-benzyl-styrene, sodium styrene sulfonate, sodium 2-sulfoxyethyl methacrylate, vinyl pyridine, aminoethyl methacrylates, 2-methacryloyloxy-trimethylammonium chloride, N,N'-methylenebisacrylamide, ethylene glycol dimethacrylates, 2,2'-(p-phenylenedioxy)-diethyl dimethacrylate, divinylbenzene, triallylamine, and methylenebis-(4-phenyl-isocyanate).
24. A contrast medium according to claim 23 wherein said microspheres comprise synthetic polymers or copolymers prepared from the group of monomers consisting of acrylic acid, methacrylic acid, ethyleneimine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate, lactic acid, glycolic acid, ε-caprolactone, acrolein, cyanoacrylate, bisphenol A, epichlorhydrin, hydroxyalkylacrylates, siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol, hydroxyalkyl-methacrylates, N-substituted acrylamides, N-substituted methacrylamides, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene, p-amino-styrene, p-amino-benzyl-styrene, sodium styrene sulfonate, sodium 2-sulfoxyethylmethacrylate, vinyl pyridine, aminoethyl methacrylates, and 2-methacryloyloxy-trimethylammonium chloride.
25. A contrast medium according to claim 22 wherein said microspheres comprise synthetic polymers or copolymers selected from the group consisting of polyacrylic acid, polyethyleneimine, polymethacrylic acid, polymethylmethacrylate, polysiloxane, polydimethylsiloxane, polylactic acid, poly(ε-capro-lactone), epoxy resin, poly(ethylene oxide), poly(ethylene glycol), polyamide, polyvinylidene-polyacrylonitrile, polyvinylidene-polyacrylonitrile-polymethylmethacrylate, and polystyrene-polyacrylonitrile.
26. A contrast medium according to claim 22 wherein said microspheres comprise a polyvinylidene-polyacrylonitrile copolymer.
27. A contrast medium according to claim 22 wherein said microspheres comprise a polyoxypropylene-polyoxyethylene copolymer.
28. A contrast medium according to claim 22 wherein said microspheres are prepared by a heat expansion process.
29. A contrast medium according to claim 22 wherein said perfluorocarbon gas is selected from the group consisting of perfluorocarbons having between 1 and about 9 carbon atoms and between about 4 and about 20 fluorine atoms.
30. A contrast medium according to claim 29 wherein said perfluorocarbon gas is selected from the group consisting of perfluorocarbons having less than about 4 carbon atoms and less than about 10 fluorine atoms.
31. A contrast medium according to claim 29 wherein said perfluorocarbon gas is C3 F8.
32. A contrast medium according to claim 29 wherein said perfluorocarbon gas is C4 F10.
33. A contrast medium according to claim 29 wherein said perfluorocarbon gas is C5 F12.
34. A contrast medium according to claim 29 wherein said perfluorocarbon gas is C6 F14.
35. A contrast medium according to claim 22 further comprising a thickening or suspending agent.
36. A contrast medium according to claim 35 wherein said thickening or suspending agent is selected from the group consisting of cellulose, carboxymethylcellulose, methylcellulose, and methylhydroxycellulose.
37. A contrast medium according to claim 36 wherein said thickening or suspending agent is methylcellulose.
38. A contrast medium according to claim 22 further comprising a compound selected from the group antacids, antiflatulents, antifoaming agents, and surfactants.
39. A contrast medium according to claim 38 wherein said compound selected from the group antacids, antiflatulents, antifoaming agents, and surfactants, comprises a polymeric siloxane.
40. A contrast medium according to claim 39 wherein said polymeric siloxane is dimethylpolysiloxane.
41. A contrast medium according to claim 40 wherein said dimethylpolysiloxane is simethicone.
42. A contrast medium according to claim 22 wherein said microspheres comprise a polyoxypropylene-polyoxyethylene copolymer, and said perfluorocarbon gas comprises C5 F12, and wherein said contrast medium further comprises methylcellulose and simethicone.
44. An aqueous suspension of microspheres according to claim 43 wherein said microspheres comprise synthetic polymers or copolymers prepared from the group of monomers consisting of acrylic acid, methacrylic acid, ethyleneimine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate, lactic acid, glycolic acid, ε-caprolactone, acrolein, cyanoacrylate, bisphenol A, epichlorhydrin, hydroxyalkylacrylates, siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol, hydroxyalkyl-methacrylates, N-substituted acrylamides, N-substituted methacrylamides, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene, p-amino-styrene, p-amino-benzyl-styrene, sodium styrene sulfonate, sodium 2-sulfoxyethyl methacrylate, vinyl pyridine, aminoethyl methacrylates, 2-methacryloyloxy-trimethylammonium chloride, N,N'-methylenebisacrylamide, ethylene glycol dimethacrylates, 2,2'-(p-phenylenedioxy)-diethyl dimethacrylate, divinylbenzene, triallylamine, and methylenebis-(4-phenyl-isocyanate).
45. An aqueous suspension of microspheres according to claim 44 wherein said microspheres comprise synthetic polymers or copolymers prepared from the group of monomers consisting of acrylic acid, methacrylic acid, ethyleneimine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate, lactic acid, glycolic acid, ε-caprolactone, acrolein, cyanoacrylate, bisphenol A, epichlorhydrin, hydroxyalkylacrylates, siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol, hydroxyalkyl-methacrylates, N-substituted acrylamides, N-substituted methacrylamides, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene, p-amino-styrene, p-amino-benzyl-styrene, sodium styrene sulfonate, sodium 2- sulfoxyethylmethacrylate, vinyl pyridine, aminoethyl methacrylates, and 2-methacryloyloxy-trimethylammonium chloride.
46. An aqueous suspension of microspheres according to claim 43 wherein said microspheres comprise synthetic polymers or copolymers selected from the group consisting of polyacrylic acid, polyethyleneimine, polymethacrylic acid, polymethylmethacrylate, polysiloxane, polydimethylsiloxane, polylactic acid, poly(ε-capro-lactone), epoxy resin, poly(ethylene oxide), poly(ethylene glycol), polyamide, polyvinylidene-polyacrylonitrile, polyvinylidene-polyacrylonitrile-polymethylmethacrylate, and polystyrene-polyacrylonitrile.
47. An aqueous suspension of microspheres according to claim 43 wherein said microspheres comprise a polyvinylidene-polyacrylonitrile copolymer.
48. An aqueous suspension of microspheres according to claim 43 wherein said microspheres comprise a polyoxypropylene-polyoxyethylene copolymer.
49. An aqueous suspension of microspheres according to claim 43 wherein said microspheres are prepared by a heat expansion process.
50. An aqueous suspension of microspheres according to claim 43 wherein said perfluorocarbon gas is selected from the group consisting of perfluorocarbons having between 1 and about 9 carbon atoms and between about 4 and about 20 fluorine atoms.
51. An aqueous suspension of microspheres according to claim 50 wherein said perfluorocarbon gas is selected from the group consisting of perfluorocarbons having less than about 4 carbon atoms and less than about 10 fluorine atoms.
52. An aqueous suspension of microspheres according to claim 50 wherein said perfluorocarbon gas is C3 F8.
53. An aqueous suspension of microspheres according to claim 50 wherein said perfluorocarbon gas is C4 F10.
54. An aqueous suspension of microspheres according to claim 50 wherein said perfluorocarbon gas is C5 F12.
55. An aqueous suspension of microspheres according to claim 50 wherein said perfluorocarbon gas is C6 F14.
56. An aqueous suspension according to claim 43 wherein said microspheres comprise a polyoxypropylene-polyoxyethylene copolymer, and said perfluorocarbon gas comprises C5 F12, and wherein said aqueous suspension further comprises methylcellulose and simethicone.

This application is a divisional of U.S. Ser. No. 08/116,982, filed Sep. 7, 1993 now U.S. Pat. No. 5,456,900, which in turn is a divisional of U.S. Ser. No. 07/980,594, filed Jan. 19, 1993, now U.S. Pat. No. 5,281,408, which in turn is a divisional of U.S. Ser. No. 07/680,984, filed Apr. 5, 1991, now U.S. Pat. No. 5,205,290.

Computed tomography (CT) is a widespread diagnostic imaging method which measures, in its imaging process, the radiodensity (electron density) of matter. This radiodensity is depicted using CT in terms of Hounsefield Units (HU). Hounsefield Units, named after the inventor of the first CT scanner, reflect the relative absorption of CT X-rays by matter, the absorption being directly proportional to the electron density of that matter. Water, for example, has a value of 0 HU, air a value of -1000 HU, and dense cortical bone a value of +1000 HU. Because of the similarity in density of various tissues in the body, however, contrast agents have been sought to change the relative density of different tissues, and improve the overall diagnostic efficacy of this imaging method.

In the search for contrast agents for CT, researchers have generally sought to develop agents that will increase electron density in certain areas of a region of the body (positive contrast agents). Barium and iodine compounds, for example, have been developed for this purpose. For the gastrointestinal tract, barium sulfate is used extensively to increase the radiodensity of the bowel lumen on CT scans. Iodinated water soluble contrast media are also used to increase density within the gastrointestinal tract, but are not used as commonly as the barium compounds, primarily because the iodine preparations are more expensive than barium and prove less effective in increasing radiodensity within this region of the body.

Despite their widespread use, however, barium and iodine compounds are suboptimally effective as gastrointestinal contrast agents for CT. For example, if the concentration is too low, there is little contrast. Conversely, if the concentration is too high, then these radiodense contrast agents cause beam hardening artifacts which are seen as streaks on the CT images. It is also difficult to visualize the bowel mucosa with either the barium or iodine contrast agents.

In an attempt to improve upon the efficacy of contrast agents for the gastrointestinal tract, lipid emulsions that are capable of decreasing electron density (negative contrast agents) have been developed. Because lipids have a lower electron density than water, lipids provide a negative density on CT (a negative HU value). While these lipid emulsions appear to be more effective than the barium and iodine agents at improving visualization of the mucosa of the bowel, these contrast agents have limitations. First, there is a limitation to the concentration of lipid which a patient can tolerably drink, which puts a limit on the change in density (or HU) which the lipid based CT contrast agent can provide. Lipid emulsions are also frequently expensive. Furthermore, these lipid formulations are generally perishable, which provides for packaging and storage problems.

New and/or better contrast agents for computed tomography imaging are needed. The present invention is directed toward this important end.

The present invention is directed to computed tomography imaging, and more particularly to the use of a contrast medium comprising a substantially homogeneous aqueous suspension of low density microspheres to image the gastrointestinal region and other body cavities of a patient. In one embodiment, the low density microspheres are gas-filled.

Specifically, the present invention pertains to methods of providing an image of the gastrointestinal region or other body cavities of a patient comprising (i) administering to the patient the aforementioned contrast medium, and (ii) scanning the patient using computed tomography imaging to obtain visible images of the gastrointestinal region or other body cavities.

The present invention is further directed to methods for diagnosing the presence of diseased tissue in the gastrointestinal region or other body cavities of a patient comprising (i) administering to the patient the aforementioned contrast medium, and (ii) scanning the patient using computed tomography imaging to obtain visible images of any diseased tissue in the patient.

The present invention also provides diagnostic kits for computed tomography imaging of the gastrointestinal region or other body cavities which include the subject contrast medium.

A wide variety of different low density microspheres may be utilized in the present invention. Preferably, the microspheres (which are small spheres having a central void or cavity), are composed of biocompatible synthetic polymers or copolymers prepared from monomers such as acrylic acid, methacrylic acid, ethyleneimine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate (HEMA), lactic acid, glycolic acid, ε-caprolactone, acrolein, cyanoacrylate, bisphenol A, epichlorhydrin, hydroxyalkylacrylates, siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol, hydroxyalkyl-methacrylates, N-substituted acrylamides, N-substituted methacrylamides, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene, p-amino-styrene, p-amino-benzylstyrene, sodium styrene sulfonate, sodium 2-sulfoxyethylmethacrylate, vinyl pyridine, aminoethyl methacrylates, 2-methacryloyloxy-trimethylammonium chloride, and polyvinylidene, as well polyfunctional crosslinking monomers such as N,N'-methylenebisacrylamide, ethylene glycol dimethacrylates, 2,2'-(p-phenylenedioxy)-diethyl dimethacrylate, divinylbenzene, triallylamine and methylenebis-(4-phenyl-isocyanate), including combinations thereof. Preferable polymers include polyacrylic acid, polyethyleneimine, polymethacrylic acid, polymethylmethacrylate, polysiloxane, polydimethylsiloxane, polylactic acid, poly(ε-caprolactone), epoxy resin, poly(ethylene oxide), poly(ethylene glycol), and polyamide (nylon). Preferable copolymers include the following: polyvinylidene-polyacrylonitrile, polyvinylidene-polyacrylonitrile-polymethylmethacrylate, and polystyrene-polyacrylonitrile. A most preferred copolymer is polyvinylidene-polyacrylonitrile. The term biocompatible, as used herein in conjunction with the terms monomer or polymer, is employed in its conventional sense, that is, to denote polymers that do not substantially interact with the tissues, fluids and other components of the body in a adverse fashion in the particular application of interest, such as the aforementioned monomers and polymers. Other suitable biocompatible monomers and polymers will be readily apparent to those skilled in the art, once armed with the present disclosure.

The microspheres of the present invention are low density. By low density, it is meant that the microspheres of the invention have an internal void (cavity) volume which is at least about 75% of the total volume of the microsphere. Preferably, the microspheres have a void volume of at least about 80%, more preferably at least about 85%, even more preferably at least about 90%, of the total volume of the microspheres.

The microspheres may be of varying size, provided they are low density. Suitable size microspheres include those ranging from between about 1 and about 1000 microns in outside diameter, preferably between about 5 and about 70 microns in outside diameter. Most preferably, the microspheres are about 50 microns in outside diameter.

The microspheres of the invention may be prepared by various processes, as will be readily apparent to those skilled in the art, once armed with the present disclosure, such as by interfacial polymerization, phase separation and coacervation, multiorifice centrifugal preparation, and solvent evaporation. Suitable procedures which may be employed or modified in accordance with the present disclosure to prepare microspheres within the scope of the invention include those procedures disclosed in Garner et al., U.S. Pat. No. 4,179,546, Garner, U.S. Pat. No. 3,945,956, Cohrs et al., U.S. Pat. No. 4,108,806, Japan Kokai Tokkyo Koho 62 286534, British Patent No. 1,044,680, Kenaga et al., U.S. Pat. No. 3,293,114, Morehouse et al., U.S. Pat. No. 3,401,475, Walters, U.S. Pat. No. 3,479,811, Walters et al., U.S. Pat. No. 3,488,714, Morehouse et al., U.S. Pat. No. 3,615,972, Baker et al., U.S. Pat. No. 4,549,892, Sands et al., U.S. Pat. No. 4,540,629, Sands et al., U.S. Pat. No. 4,421,562, Sands, U.S. Pat. No. 4,420,442, Mathiowitz et al., U.S. Pat. No. 4,898,734, Lencki et al., U.S. Pat. No. 4,822,534, Herbig et al., U.S. Pat. No. 3,732,172, Himmel et al., U.S. Pat. No. 3,594,326, Sommerville et al., U.S. Pat. No. 3,015,128, Deasy, Microencapsulation and Related Drug Processes, Vol. 20, Chs. 9 and 10, pp. 195-240 (Marcel Dekker, Inc., N.Y., 1984), Chang et al., Canadian J. of Physiology and Pharmacology, Vol 44, pp. 115-129 (1966), and Chang, Science, Vol. 146, pp. 524-525 (1964), the disclosures of each of which are incorporated herein by reference in their entirety.

In accordance with the preferable synthesis protocol, the microspheres are prepared using a heat expansion process such as is described in Garner et al., U.S. Pat. No. 4,179,546, Garner, U.S. Pat. No. 3,945,956, Cohrs et al., U.S. Pat. No. 4,108,806, British Patent No. 1,044,680, and Japan Kokai Tokkyo Koho 62 286534. In general terms, the heat expansion process is carried out by preparing microspheres of an expandable polymer or copolymer which contain in their void (cavity) a volatile liquid. The microsphere is then heated, plasticising the microsphere and volatilizing the gas, causing the microsphere to expand to up to about several times its original size. When the heat is removed, the thermoplastic polymer retains at least some of its expanded shape. Microspheres produced by this process tend to be of particularly low density, and are thus preferred. The foregoing described process is well known in the art, and is referred to herein as the heat expansion process for preparing low density microspheres.

Polymers useful in the heat expansion process will be readily apparent to those skilled in the art and include thermoplastic polymers or copolymers, including polymers or copolymers of many of the monomers described above. Preferable of the polymers and copolymers described above include the following copolymers: polyvinylidene-polyacrylonitrile, polyvinylidene-polyacrylonitrile-polymethylmethacrylate, and polystyrene-polyacrylonitrile. A most preferred copolymer is polyvinylidene-polyacrylonitrile.

Volatile liquids useful in the heat expansion process will also be well known to those skilled in the art and include: aliphatic hydrocarbons such as ethane, ethylene, propane, propene, butane, isobutane, neopentane, acetylene, hexane, heptane; chlorofluorocarbons such as CCl3 F, CCl2 F3, CClF3, CClF2 --CCl2 F2, ##STR1## tetraalkyl silanes such as tetramethyl silane, trimethylethyl silane, trimethylisopropyl silane, and trimethyl n-propyl silane; as well as perfluorocarbons such as those having between 1 and about 9 carbon atoms and between about 4 and about 20 fluorine atoms, especially C4 F10. In general, it is important that the volatile liquid not be a solvent for the microsphere polymer or copolymer. The volatile liquid should also have a boiling point that is below the softening point of the microsphere polymer or co-polymer. Boiling points of various volatile liquids and softening points of various polymers and copolymers will be readily ascertainable to one skilled in the art, and suitable combinations of polymers or copolymers and volatile liquids will be easily apparent to the skilled artisan. By way of guidance, and as one skilled in the art would recognize, generally as the length of the carbon chain of the volatile liquid increases, the boiling point of that liquid increases. Also, by mildly preheating the microspheres in water in the presence of hydrogen peroxide prior to definitive heating and expansion may pre-soften the microsphere to allow expansion to occur more readily.

For example, to produce microspheres of the present invention, vinylidene and acrylonitrile may be copolymerized in a medium of isobutane liquid using one or more of the foregoing modified or unmodified literature procedures, such that isobutane becomes entrapped within the microspheres. When such microspheres are then heated to between about 80°C and about 120°C, the isobutane gas expands, which in turn expands the microspheres. After heat is removed, the expanded polyvinylidene and acrylonitrile copolymer microspheres remain substantially fixed in their expanded position. The resulting low density microspheres are extremely stable both dry and suspended in an aqueous media. Isobutane is utilized merely as an illustrative liquid, with the understanding that other liquids which undergo liquid/gas transitions at temperatures useful for the synthesis of these microspheres and formation of the very low density microspheres upon heating can be substituted for isobutane. Similarly, monomers other than vinylidene and acrylonitrile may be employed in preparing the microsphere.

Most preferably, the low density microspheres employed are those commercially available from Expancel, Nobel Industries, Sundsvall, Sweden, such as the EXPANCEL 551 DE™ microspheres. The EXPANCEL 551 DE™ microspheres are composed of a copolymer of vinylidene and acrylonitrile which have encapsulated therein isobutane liquid. Such microspheres are sold as a dry composition and are approximately 50 microns in size. The EXPANCEL 551 DE™ microspheres have a specific gravity of only 0.02 to 0.05, which is between one-fiftieth and one-twentieth the density of water.

In one embodiment, the microspheres of the present invention are gas-filled. By gas-filled, it is meant that at least part of the void volume inside the microspheres is occupied by the gas. Preferably, substantially all of the void volume inside the microspheres is occupied by the gas. The gas may be any type of gas, such as, for example, carbon dioxide, oxygen, nitrogen, xenon, argon, neon, helium and air. Preferably, the gas is carbon dioxide, oxygen, nitrogen, xenon, argon, neon and helium. Most preferably, the gas is inert, that is, a gas that is substantially resistant to chemical or physical action. The gas-filled low density microspheres may be synthesized under pressure such that gases are solubilized in the liquid employed in microsphere synthesis. When the pressure is removed, the gas comes out of solution to fill the microsphere void. Such microspheres can further be subjected to a heat expansion process, as described above.

For example, to produce the gas-filled microspheres of the invention, one may copolymerize vinylidene and acrylonitrile using one or more of the foregoing procedures, such as phase separation/coacervation techniques in a pressurized and/or low temperature environment (e.g., at about 300 psi, and/or at about 0°C) with a high concentration of dissolved gas (e.g., dissolved nitrogen) in solution, to form a large microsphere containing the dissolved gas. When the pressure is removed and/or the temperature raised, the gas bubbles come out of solution, forming gas filled microspheres. Such microspheres can further be subjected to a heat expansion process, as described above.

It is preferable that the microspheres be relatively stable in the gastrointestinal tract or other body cavities during the length of time necessary for completing an imaging examination. Low density microspheres prepared from the aforementioned monomer and polymer compositions will provide such stable microspheres.

In order for these microspheres to serve as effective CT contrast agents, it is necessary for the microspheres to be mixed in solution in a substantially homogeneous suspension. This can be accomplished by using thickening and suspending agents. A wide variety of thickening and suspending agents may be used to a prepare the substantially homogeneous suspensions of the microspheres. Suitable thickening and suspending agents, for example, include any and all biocompatible agents known in the art to act as thickening and suspending agents. Particularly useful are the natural thickening and suspending agents alginates, xanthan gum, guar, pectin, tragacanth, bassorin, karaya, gum arabic, casein, gelatin, cellulose, sodium carboxymethylcellulose, methylcellulose, methylhydroxycellulose, bentonite, colloidal silicic acid, and carrageenin, and the synthetic thickening and suspending agents polyethylene glycol, polypropylene glycol, and polyvinylpyrrolidone. As those skilled in the art would recognize, once armed with the present disclosure, the suspending agents may be formulated, if desired, to be either less dense than water or of neutral density, so as to not subtract from the density lowering capabilities of the microspheres. For example, a cellulose suspension may have a somewhat lower density than water, e.g., a 2 weight % cellulose solution with 0.25 weight % xanthan gum has a density of 0.95. The thickening and suspending agents may be employed in varying amounts, as those skilled in the art would recognize, but preferably are employed in amounts of about 0.25 to about 10 weight % preferably about 0.5 to about 5 weight % of the contrast medium.

The substantially homogeneous, aqueous suspension of low density microspheres of the invention are useful as CT contrast agents. These agents are capable of producing negative contrast in the gastrointestinal tract or in other body cavities, providing effective contrast enhancement and improved visualization in these areas of the body. Specifically, the present invention is directed to a method of providing an image of or detecting diseased tissue in the gastrointestinal region and other body cavities of a patient, the method comprising administering to the patient a contrast medium comprising a substantially homogeneous aqueous solution of low density microspheres, and scanning the patient using computed tomography imaging to obtain visible images of the gastrointestinal region or other body cavities or of diseased tissue in these areas of the body.

The phrase gastrointestinal region or gastrointestinal tract, as used herein, includes the region of a patient defined by the esophagus, stomach, small and large intestines, and rectum. The phrase other body cavities, as used herein, includes any region of the patient, other than the gastrointestinal region, having an open passage, either directly or indirectly, to the external environment, such regions including the sinus tracts, the fallopian tubes, the bladder, etc. The patient can be any type of mammal, but most preferably is a human.

As one skilled in the art would recognize, administration of the contrast medium to the patient may be carried out in various fashions, such as orally, rectally, or by injection. When the region to be scanned is the gastrointestinal region, administration of the contrast medium of the invention is preferably carried out orally or rectally. When other body cavities such as the fallopian tubes or sinus tracts are to be scanned, administration is preferably by injection. As would also be recognized by one skilled in the art, wide variations in the amounts of the gas filled microspheres can be employed in the methods and kits of the invention, with the precise amounts varying depending upon such factors as the mode of administration (e.g., oral, rectal, by injection), and the specific body cavity and portion thereof for which an image is sought (e.g., the stomach of the gastrointestinal tract). Typically, dosage is initiated at lower levels and increased until the desired contrast enhancement is achieved.

For CT imaging, it is generally desirable to decrease the density of the lumen of the gastrointestinal tract or other body cavities to at least about -30 HU, the maximum decrease being limited by the practical amount of the microspheres which may be suspended in the aqueous media and ingested by the patient. In general, a decrease in HU to between about -30 HU and about -150 HU is sufficient to mark the inside of the bowel or other body cavity. By way of general guidance, and as a rough rule of thumb, to decrease the density of the microsphere aqueous suspension to about -150 HU, the microspheres must occupy about 15% of the total volume of the aqueous suspension. To achieve a density of about -50 HU, the microspheres must occupy about 5% of the total volume of the solution. The volume of contrast agent administered to the patient is typically between about 50 to about 1000 cc. Using the EXPANCEL 551 DE™ microspheres as a model, it has been found that about 0.6 grams of the dry 50 micron spheres in 100 cc of aqueous suspension is sufficient to decrease the density of the suspension to nearly -150 HU.

It should be noted that smaller microspheres are generally more stable in suspension, but usually have higher specific gravity than larger microspheres. Therefore, for CT, the size and particular microspheres, as well as the suspending media (thickening and suspending agents) should selected to minimize specific gravity, while maximizing the stability of the suspension.

The contrast medium utilized of the present invention may also be employed with other conventional additives suitable for use in the applications contemplated for the subject invention.

Where gastrointestinal applications are concerned, such additives include conventional biocompatible anti-gas agents, osmolality raising agents, gastrointestinal transit agents (the later agents serving to decrease the gastrointestinal transit time and increase the rate of gastrointestinal emptying) and, in some instances, gas-forming agents.

As used herein the term anti-gas agent is a compound that serves to minimize or decrease gas formation, dispersion and/or adsorption. A number of such agents are available, including antacids, antiflatulents, antifoaming agents, and surfactants. Such antacids and antiflatulents include, for example, activated charcoal, aluminum carbonate, aluminum hydroxide, aluminum phosphate, calcium carbonate, dihydroxyaluminum sodium carbonate, magaldrate magnesium oxide, magnesium trisilicate, simethicone, sodium carbonate, loperamide hydrochloride, diphenoxylate, hydrochloride with atropine sulfate, Kaopectate™ (kaolin) and bismuth salts. Suitable antifoaming agents useful as anti-gas agents include simethicone, protected simethicone, siloxyalkylene polymers, siloxane glycol polymers, polyoxypropylene-polyoxyethylene copolymers, polyoxyalkylene amines and imines, branched polyamines, mixed oxyalkylated alcohols, finely divided silica either alone or mixed with dimethyl polysiloxane, sucroglycamides (celynols), polyoxylalkylated natural oils, halogenated silicon-containing cyclic acetals, lauryl sulfates, 2-lactylic acid esters of unicarboxylic acids, triglyceride oils. Particles of polyvinyl chloride or silica may also function as anti-foaming agents in the subject invention. Suitable surfactants include perfluorocarbon surfactants, such as, for example, DuPont Zonyl™ perfluoroalkyl surfactants known as Zonyl™ RP or Zonyl™ NF, available from DuPont, Chemicals and Pigments Division, Jackson Laboratory, Deepwater, N.J. 08023. Of course, as those skilled in the art will recognize, any anti-gas agents employed must be suitable for use within the particular biological system of the patient in which it is to be used. The concentration of such anti-gas agents may vary widely, as desired, as will be readily apparent to those skilled in the art. Typically, however, such agents are employed in concentrations of between about 20 and about 2000 ppm, most preferably in concentrations between about 50 and about 1000 ppm.

Suitable osmolality raising agents include polyols and sugars, for example, mannitol, sorbitol, arabitol, xylitol, glucose, sucrose, fructose, dextrose, and saccharine, with mannitol and sorbitol being most preferred. The concentration of such osmolality raising agents may vary, as desired, however, generally a range of about 5 to about 70 g/l, preferably about 30 to about 50 g/l of the contrast medium. Such compounds may also serve as sweeteners for the ultimate formulation, if desired.

Gastrointestinal transit agents include algin, as well as many of the compounds listed above as thickening and suspending agents, with algin being most preferred. The amount of such agents will, of course, vary as those skilled in the art will recognize, but generally will be employed in an amount of between about 5 and about 40 mmol/l.

In some applications, it may be helpful to incorporate gas-forming agents into the contrast medium. Gas-forming agents include sodium bicarbonate, calcium carbonate, aminomalonate, and the like, which will form gas, for example, upon introduction into the gastrointestinal tract. Such gas-forming agents will serve to distend the gastrointestinal tract and create a form of "double contrast" between the gas and the low density microspheres.

Kits useful for computed tomography imaging of the gastrointestinal region or other body cavities in accordance with the present invention comprise low density microspheres, and a thickening or suspending agent, in addition to conventional computed tomography imaging kit components. Such conventional computed tomography kit components will be readily apparent to those skilled in the art, once armed with the present disclosure.

Where imaging of the gastrointestinal region is contemplated, such computed tomography kit components may include, for example, anti-gas agents, osmolality raising agents, gastrointestinal transit agents and, in some instances, gas-forming agents.

The computed tomography imaging principles and techniques which are employed are conventional and are described, for example, in Computed Body Tomography, Lee, J. K. T., Sagel, S. S., and Stanley, R. J., eds., Ch. 1, pp. 1-7 (Raven Press, New York 1933). Any of the various types of computed tomography imaging devices can be used in the practice of the invention, the particular type or model of the device not being critical to the method of the invention.

The present invention is further described in the following Examples. Examples 1-7 are prophetic examples based at least in part on the teachings of Garner, U.S. Pat. No. 3,945,956, and describe the preparation of microspheres by a heat expansion process. Examples 8-9 are actual examples that describe the preparation of contrast media of the invention. The following Examples are not to be construed as limiting the scope of the appended Claims.

PAC Example 1

A vessel is filled with 50 parts by weight of deionized water and 6 parts by weight of a 25 percent by weight aqueous colloidal silica dispersion. A mixture of 0.3 parts by weight of a 10 weight percent solution of diethylamine-adipic acid copolymer is added to the above. A condensation reaction occurs creating a mixture having a viscosity of about 95 centipoise at a temperature of about 27°C Potassium dichromate (0.05 parts by weight) is added to the aqueous phase as a water phase polymerization inhibitor. Sodium chloride (1 part by weight) is also present in the water phase; hydrochloric acid is used to adjust the pH of the aqueous phase to 4∅ Styrene (15 parts by weight), acrylonitrile (10 parts by weight), a mixture of diethylbenzene and divinylbenzene (0.21 parts by weight comprising a 55:45 percent mixture of each respectively), 6.25 parts by weight of isobutane and 0.07 parts by weight of secondary butyl peroxydicarbonate. The oil phase is added to the water phase with violent agitation created by a shearing blade rotating at 10,000 RPM employing a mixing blender. After the material has reacted for about 30 minutes, the mixture is poured into a citrate bottle and capped. The material is maintained at about 50°C in the citrate bath for about 24 hours and agitated throughout this time. At the end of 24 hours, the reaction bottle is cooled and the material is removed, washed and dried. A portion of the microspheres are set aside and the remainder are heated in an air oven for a period of about 30 minutes at about 150°C A sample of the dry unexpanded and dry expanded microspheres are then studied by a Coulter Counter. The dry unexpanded microspheres have a size of about 2 to 12 microns. About half of the microspheres exposed to the heating process show expansion.

The procedures of Example 1 are substantially repeated with the exception that 1 part by weight of methanol is added to the reaction mixture. The dry unexpanded and dry heat expanded microspheres are then studied by Coulter Counter. The dry unexpanded microspheres measure about 8 to 10 microns in size. Essentially all the microspheres exposed to heat expand.

The procedures of Example 2 are substantially repeated except that after synthesis of the microspheres, a slurry of the microspheres is added to an aqueous solution containing 35 weight percent hydrogen peroxide. This slurry is heated to a temperature of about 50°C for about 3.5 hours and subsequently cooled and air-dried. A portion of the microspheres is then added to water and heated to a temperature of about 75°C with vigorous stirring for about 30 seconds. Study with Coulter Counter shows that pretreatment with hydrogen peroxide enables a lower temperature and briefer period of heating to be used for definitive heating and expansion.

The procedures of Example 1 are substantially repeated with the exception that 5 parts by weight of ethanol are included in the reaction mixture forming the microspheres. Coulter Counter shows that the dry unexpanded particles have diameters of about 24 to 28 microns. When heated, essentially all of the microspheres expand.

The procedures of Example 1 are substantially repeated with the exception that in place of methanol, 1 part by weight of normal butanol is used. The diameter of the dry unexpanded microspheres is about 10 to 12 microns and on heating, essentially all of the microspheres expand.

The procedures of Example 1 are substantially repeated with the exception that the volatile liquid isobutane is replaced with perfluorocarbon liquid (C4 F10). The remainder of the process is similar. The resulting microspheres are filled with perfluorocarbon liquid rather than isobutane.

The procedures of Example 1 are substantially repeated with the exception that the reaction is conducted in a pressurized vessel enabling pressurization with gas and simultaneous agitation (agitation accomplished with either sonication or shearing blades within the device). As the microspheres are formed within the device, the vessel is pressurized to about 300 psi with nitrogen gas. The vessel is then depressurized, allowing the gas to come out of solution. The microspheres are then subjected to heat as substantially described in Example 1.

A suspension of 2% of 22 micron fiber length cellulose in 0.25% xanthan gum in water was prepared. Scans by CT showed a CT density of about -45 HU for the cellulose suspension. EXPANCEL 551 DE™ polyvinylidene-polyacrylonitrile microspheres, 50 microns in size, were then suspended in the aqueous cellulose suspension at a concentration of 0.4 grams of microspheres per 100 ml of cellulose suspension using vigorous shaking. The resulting suspension remained substantially homogeneous for about 10 minutes. The suspension was again shaken vigorously to render it substantially homogeneous and scanned immediately by CT. The resulting CT density as measured by the scanner was about -96 HU.

A suspension of 1% algin was prepared. EXPANCEL 551 DE™ microspheres were added to the algin suspension in an amount of about 0.2 grams of microspheres per deciliter of algin suspension, using vigorous shaking, to form a substantially homogeneous suspension. The resulting suspension was found to have much greater stability than the cellulose/microsphere suspension of Example 1. The algin/microsphere suspension was then scanned by CT, with the density as measured by the scanner being about -40 HU.

Various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended Claims.

Unger, Evan C.

Patent Priority Assignee Title
10022460, Dec 31 2014 Lantheus Medical Imaging, Inc. Lipid-encapsulated gas microsphere compositions and related methods
10022462, Feb 08 2010 Lantheus Medical Imaging, Inc. Methods and apparatus for synthesizing imaging agents, and intermediates thereof
10125106, Feb 13 2004 Lantheus Medical Imaging, Inc. Contrast agents for myocardial perfusion imaging
10220104, Jul 06 2016 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
10245332, Feb 29 2008 Lantheus Medical Imaging, Inc. Contrast agents for applications including perfusion imaging
10500293, Aug 10 2012 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
10583207, Dec 31 2014 LANTHEUS MEDICAL IMAGING, INC Lipid-encapsulated gas microsphere compositions and related methods
10583208, Jul 06 2016 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
10588988, May 04 2016 Lantheus Medical Imaging, Inc. Methods and devices for preparation of ultrasound contrast agents
10842892, Feb 08 2010 LANTHEUS MEDICAL IMAGING, INC Methods and apparatus for synthesizing imaging agents, and intermediates thereof
10889550, Feb 13 2004 Lantheus Medical Imaging, Inc. Contrast agents for myocardial perfusion imaging
11266749, Jul 06 2016 LANTHEUS MEDICAL IMAGING, INC Methods for making ultrasound contrast agents
11266750, Jul 06 2016 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
11344636, Jul 06 2016 LANTHEUS MEDICAL IMAGING, INC Methods for making ultrasound contrast agents
11395856, Dec 31 2014 Lantheus Medical Imaging, Inc. Lipid-encapsulated gas microsphere compositions and related methods
11529431, Jul 06 2016 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
11744906, Aug 10 2012 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
11857646, Jul 06 2016 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
11925695, Jul 06 2016 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
11992358, Feb 13 2019 The Regents of the University of California Multimodality anthropomorhic phantom apparatus
12097270, May 04 2016 Lantheus Medical Imaging, Inc. Methods and devices for preparation of ultrasound contrast agents
5688490, Feb 15 1991 Bracco International B.V. Mucoadhesive compositions for increasing the ultrasonic image contrast of the digestive tract
5733572, Dec 22 1989 IMARX THERAPEUTICS, INC Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles
5736121, May 23 1994 IMARX THERAPEUTICS, INC Stabilized homogenous suspensions as computed tomography contrast agents
5741478, Nov 19 1994 Quadrant Drug Delivery Limited Preparation of hollow microcapsules by spray-drying an aqueous solution of a wall-forming material and a water-miscible solvent
5769080, Dec 22 1989 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Gas filled liposomes and stabilized gas bubbles and their use as ultrasonic contrast agents
5770222, Dec 22 1989 CEREVAST THERAPEUTICS, INC Therapeutic drug delivery systems
5776429, Dec 22 1989 LANTHEUS MEDICAL IMAGING, INC Method of preparing gas-filled microspheres using a lyophilized lipids
5792445, Feb 15 1991 Bracco International B.V. Polymers and copolymers of acrylic acid MRI of the digestive tract of patients
5830430, Feb 21 1995 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Cationic lipids and the use thereof
5837221, Jul 29 1996 ACUSPHERE, INC Polymer-lipid microencapsulated gases for use as imaging agents
5846517, Sep 11 1996 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Methods for diagnostic imaging using a renal contrast agent and a vasodilator
5853698, Mar 05 1996 Acusphere, Inc. Method for making porous microparticles by spray drying
5853752, Dec 22 1989 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Methods of preparing gas and gaseous precursor-filled microspheres
5855865, Jul 02 1993 Molecular Biosystems, Inc. Method for making encapsulated gas microspheres from heat denatured protein in the absence of oxygen gas
5874062, Apr 05 1991 IMARX THERAPEUTICS, INC Methods of computed tomography using perfluorocarbon gaseous filled microspheres as contrast agents
5876696, Jan 25 1993 SONUS PHARMACEUTICALS, INC Composition comprising a fluorine containing surfactant and perfluoropentane for ultrasound
5922304, Dec 22 1989 CEREVAST MEDICAL, INC Gaseous precursor filled microspheres as magnetic resonance imaging contrast agents
5957848, Oct 10 1992 Quadrant Drug Delivery Limited Preparation of further diagnostic agents
5965109, Aug 02 1994 Molecular Biosystems, Inc. Process for making insoluble gas-filled microspheres containing a liquid hydrophobic barrier
5985246, Dec 22 1989 LANTHEUS MEDICAL IMAGING, INC Contrast agents for ultrasonic imaging and methods for preparing the same
5997898, Jun 06 1995 IMARX THERAPEUTICS, INC Stabilized compositions of fluorinated amphiphiles for methods of therapeutic delivery
6001335, Dec 22 1989 LANTHEUS MEDICAL IMAGING, INC Contrasting agents for ultrasonic imaging and methods for preparing the same
6015546, Oct 10 1992 Quadrant Drug Delivery Limited Preparation of further diagnostic agents
6017310, Oct 04 1996 QUADRANT HEALTHCARE UK LIMITED Use of hollow microcapsules
6022525, Apr 10 1991 Quadrant Drug Delivery Limited Preparation of diagnostic agents
6028066, May 06 1997 IMARX THERAPEUTICS, INC Prodrugs comprising fluorinated amphiphiles
6033646, Dec 22 1989 LANTHEUS MEDICAL IMAGING, INC Method of preparing fluorinated gas microspheres
6039557, Dec 22 1989 LANTHEUS MEDICAL IMAGING, INC Apparatus for making gas-filled vesicles of optimal size
6056938, Feb 21 1995 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Cationic lipids and the use thereof
6068600, Dec 06 1996 QUADRANT HEALTHCARE UK LIMITED Use of hollow microcapsules
6071494, Sep 11 1996 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Methods for diagnostic imaging using a contrast agent and a renal vasodilator
6071495, Dec 22 1989 LANTHEUS MEDICAL IMAGING, INC Targeted gas and gaseous precursor-filled liposomes
6088613, Dec 22 1989 CEREVAST THERAPEUTICS, INC Method of magnetic resonance focused surgical and therapeutic ultrasound
6090800, May 06 1997 IMARX THERAPEUTICS, INC Lipid soluble steroid prodrugs
6117414, Apr 05 1991 IMARX THERAPEUTICS, INC Method of computed tomography using fluorinated gas-filled lipid microspheres as contract agents
6120751, Mar 21 1997 IMARX THERAPEUTICS, INC Charged lipids and uses for the same
6123923, Dec 18 1997 CEREVAST THERAPEUTICS, INC Optoacoustic contrast agents and methods for their use
6123965, Jan 26 1996 PEROSPHERE INC Methods and compositions for enhancing the bioadhesive properties of polymers
6132699, Mar 05 1996 Acusphere, Inc. Microencapsulated fluorinated gases for use as imaging agents
6139819, Jun 07 1995 CEREVAST MEDICAL, INC Targeted contrast agents for diagnostic and therapeutic use
6143276, Mar 21 1997 IMARX THERAPEUTICS, INC Methods for delivering bioactive agents to regions of elevated temperatures
6146657, Dec 22 1989 LANTHEUS MEDICAL IMAGING, INC Gas-filled lipid spheres for use in diagnostic and therapeutic applications
6156292, Sep 17 1991 GE HEALTHCARE AS Gaseous ultrasound contrast media and method for selecting gases for use as ultrasound contrast media
6165482, Feb 07 1997 Gastrointestinal drug composition
6231834, Jun 07 1995 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Methods for ultrasound imaging involving the use of a contrast agent and multiple images and processing of same
6245319, Jan 25 1993 SONUS PHARMACEUTICALS, INC Colloidal dispersions of perfluoropentane
6280705, Jul 30 1993 TARGESON, INC ; TARGESON INC Kits & systems for ultrasonic imaging
6309623, Sep 29 1997 Novartis Pharma AG Stabilized preparations for use in metered dose inhalers
6315981, Dec 22 1989 CEREVAST THERAPEUTICS, INC Gas filled microspheres as magnetic resonance imaging contrast agents
6344182, Oct 10 1992 Quadrant Drug Delivery Limited Preparation of diagnostic agents by spray drying
6368586, Jan 26 1996 PEROSPHERE INC Methods and compositions for enhancing the bioadhesive properties of polymers
6403056, Mar 21 1997 CEREVAST MEDICAL, INC Method for delivering bioactive agents using cochleates
6414139, Sep 03 1996 IMARX THERAPEUTICS, INC Silicon amphiphilic compounds and the use thereof
6416740, May 13 1997 BRISTOL-MYERS SQUIBB MEDICAL IMAGING, INC Acoustically active drug delivery systems
6416741, Oct 10 1992 Quadrant Drug Delivery Limited Preparation of further diagnostic agents
6433040, Sep 29 1997 Novartis Pharma AG Stabilized bioactive preparations and methods of use
6443898, Dec 22 1989 CEREVAST MEDICAL, INC Therapeutic delivery systems
6444660, May 06 1997 CEREVAST THERAPEUTICS, INC Lipid soluble steroid prodrugs
6461586, Dec 22 1989 CEREVAST THERAPEUTICS, INC Method of magnetic resonance focused surgical and therapeutic ultrasound
6479034, Dec 22 1989 LANTHEUS MEDICAL IMAGING, INC Method of preparing gas and gaseous precursor-filled microspheres
6521211, Jun 07 1995 BRISTOL-MYERS SQUIBB MEDICAL IMAGING, INC Methods of imaging and treatment with targeted compositions
6528039, Apr 05 1991 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Low density microspheres and their use as contrast agents for computed tomography and in other applications
6537246, Jun 18 1997 CEREVAST THERAPEUTICS, INC Oxygen delivery agents and uses for the same
6548047, Sep 15 1997 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Thermal preactivation of gaseous precursor filled compositions
6551576, Dec 22 1989 LANTHEUS MEDICAL IMAGING, INC Container with multi-phase composition for use in diagnostic and therapeutic applications
6565885, Sep 29 1997 Novartis Pharma AG Methods of spray drying pharmaceutical compositions
6569404, Jan 25 1993 GE HEALTHCARE AS Phase shift colloids as ultrasound contrast agents
6569405, Apr 10 1991 Quadrant Drug Delivery Limited Preparation of diagnostic agents
6572840, Jul 28 1999 LANTHEUS MEDICAL IMAGING, INC Stable microbubbles comprised of a perfluoropropane encapsulated lipid moiety for use as an ultrasound contrast agent
6576220, Mar 11 1994 CEREVAST MEDICAL, INC Non-invasive methods for surgery in the vasculature
6620404, Sep 17 1991 GE HEALTHCARE AS Gaseous ultrasound contrast media and method for selecting gases for use as ultrasound contrast media
6623722, Nov 19 1994 Quadrant Drug Delivery Limited Spray-drying microcapsules using an aqueous liquid containing a volatile liquid
6638495, Sep 29 1997 Novartis Pharma AG Stabilized preparation for use in metered dose inhalers
6638767, May 01 1996 CEREVAST THERAPEUTICS, INC Methods for delivering compounds into a cell
6716412, Sep 15 1997 CEREVAST MEDICAL, INC Methods of ultrasound treatment using gas or gaseous precursor-filled compositions
6723303, Sep 17 1991 GE HEALTHCARE AS Ultrasound contrast agents including protein stabilized microspheres of perfluoropropane, perfluorobutane or perfluoropentane
6743779, Nov 29 1994 CEREVAST THERAPEUTICS, INC Methods for delivering compounds into a cell
6773696, Apr 05 1991 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Contrast agent comprising low density microspheres
6808720, Mar 21 1997 CEREVAST THERAPEUTICS, INC Charged lipids and uses for the same
6838074, Aug 08 2001 LANTHEUS MEDICAL IMAGING, INC Simultaneous imaging of cardiac perfusion and a vitronectin receptor targeted imaging agent
6875420, Sep 17 1991 GE HEALTHCARE AS Method of ultrasound imaging
6884407, Sep 11 1996 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Methods for diagnostic imaging involving the use of a contrast agent and a coronary vasodilator
6939530, Oct 10 1992 Quadrant Drug Delivery Limited Preparation of further diagnostic agents
6946117, Sep 29 1997 Novartis Pharma AG Stabilized preparations for use in nebulizers
6998107, Apr 05 1991 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Composition comprising low density microspheres
7078015, Dec 22 1989 ImaRx Therapeutics, Inc. Ultrasound imaging and treatment
7083572, Nov 30 1993 Bristol-Myers Squibb Medical Imaging, Inc. Therapeutic delivery systems
7105151, Jun 18 1997 CEREVAST THERAPEUTICS, INC Oxygen delivery agents and uses for the same
7138104, Aug 08 2001 LANTHEUS MEDICAL IMAGING, INC Simultaneous imaging of cardiac perfusion and a vitronectin receptor targeted imaging agent
7205343, Sep 29 1997 Novartis Pharma AG Stabilized bioactive preparations and method of use
7211240, Mar 01 2002 Bracco Suisse SA Multivalent constructs for therapeutic and diagnostic applications
7261876, Mar 01 2002 Bracco Suisse SA Multivalent constructs for therapeutic and diagnostic applications
7306787, Sep 29 1997 Novartis AG Engineered particles and methods of use
7329402, Jun 07 1995 ImaRx Pharmaceutical Corp. Methods of imaging and treatment
7344702, Feb 13 2004 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Contrast agents for myocardial perfusion imaging
7344705, Apr 05 1991 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Composition comprising low density microspheres
7358226, Aug 27 2003 Regents of the University of California, The Ultrasonic concentration of drug delivery capsules
7368102, Dec 19 2001 BGP Products Operations GmbH Pulmonary delivery of aminoglycosides
7368167, Jun 17 2004 Henkel IP & Holding GmbH Ultra low density thermally clad microspheres and method of making same
7393544, Sep 29 1997 Novartis AG Dispersion for pulmonary delivery of a bioactive agent
7442388, May 10 2000 Novartis AG Phospholipid-based powders for drug delivery
7452551, Oct 30 2000 CEREVAST MEDICAL, INC Targeted compositions for diagnostic and therapeutic use
7485283, Apr 28 2004 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Contrast agents for myocardial perfusion imaging
7534452, Oct 16 2003 Encapsule Medical, LLC Post-biopsy cavity treatment implants and methods
7537788, Jul 25 2003 Encapsule Medical, LLC Post-biopsy cavity treatment implants and methods
7612033, Nov 29 1994 CEREVAST THERAPEUTICS, INC Methods for delivering compounds into a cell
7628978, Sep 29 1997 Novartis Pharma AG Stabilized preparations for use in metered dose inhalers
7666979, Mar 01 2002 Bracco Suisse SA Methods for preparing multivalent constructs for therapeutic and diagnostic applications and methods of preparing the same
7744852, Feb 09 2007 Encapsule Medical, LLC Methods and systems for marking post biopsy cavity sites
7780948, Jul 25 2003 Encapsule Medical, LLC Post biopsy cavity treatment implants and methods
7794693, Mar 01 2002 Bracco Suisse SA Targeting vector-phospholipid conjugates
7824659, Aug 10 2005 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Methods of making radiolabeled tracers and precursors thereof
7854919, Mar 01 2002 Bracco Suisse SA Multivalent constructs for therapeutic and diagnostic applications
7871598, May 10 2000 Novartis AG Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use
7910088, Mar 01 2002 Bracco Suisse SA Multivalent constructs for therapeutic and diagnostic applications
7985402, Mar 01 2002 Bracco Suisse SA Targeting vector-phospholipid conjugates
8012457, Jun 04 2004 ACUSPHERE, INC Ultrasound contrast agent dosage formulation
8080263, Sep 29 1997 Novartis Pharma AG Dispersion for pulmonary delivery of a bioactive agent
8084056, Jan 14 1998 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Preparation of a lipid blend and a phospholipid suspension containing the lipid blend
8092779, Jul 25 2003 Encapsule Medical, LLC Post-biopsy cavity treatment implants and methods
8168223, Sep 29 1997 Novartis AG Engineered particles and methods of use
8226929, Feb 13 2004 Bristol-Myers Squibb Pharma Company Contrast agents for myocardial perfusion imaging
8246934, Feb 05 2008 Novartis AG Respiratory dispersion for metered dose inhalers comprising perforated microstructures
8263042, Apr 28 2004 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Contrast agents for myocardial perfusion imaging
8349294, May 10 2000 Novartis AG Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use
8404217, May 10 2000 Novartis AG Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use
8491630, Jul 25 2003 Encapsule Medical, LLC Post-biopsy cavity treatment implants and methods
8551001, Jun 20 2005 Bayer HealthCare LLC Methods for determining lumen occlusion
8551450, Mar 01 2002 Bracco Suisse SA Targeting vector-phospholipid conjugates
8585616, Oct 09 2009 Bayer HealthCare LLC Methods and apparatus for determining fallopian tube occlusion
8586005, Jun 04 2004 Acusphere, Inc. Ultrasound contrast agent dosage formulation
8623822, Mar 01 2002 Bracco Suisse SA KDR and VEGF/KDR binding peptides and their use in diagnosis and therapy
8632753, Mar 01 2002 Bracco Suisse SA; Dyax Corp. Multivalent constructs for therapeutic and diagnostic applications
8642010, Mar 01 2002 Takeda Pharmaceutical Company Limited KDR and VEGF/KDR binding peptides and their use in diagnosis and therapy
8658205, Jan 14 1998 Lantheus Medical Imaging, Inc. Preparation of a lipid blend and a phospholipid suspension containing the lipid blend
8663603, Mar 01 2002 Dyax Corp Multivalent constructs for therapeutic and diagnostic applications
8685441, Jan 14 1998 Lantheus Medical Imaging, Inc. Preparation of a lipid blend and a phospholipid suspension containing the lipid blend
8709484, May 10 2000 Novartis AG Phospholipid-based powders for drug delivery
8715623, Dec 19 2001 BGP Products Operations GmbH Pulmonary delivery of aminoglycoside
8747892, Jan 14 1998 Lantheus Medical Imaging, Inc. Preparation of a lipid blend and a phospholipid suspension containing the lipid blend
8777876, Oct 09 2009 Bayer HealthCare LLC Methods and apparatus for determining fallopian tube occlusion
8877162, May 10 2000 Novartis AG Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery
8936777, Feb 08 2010 LANTHEUS MEDICAL IMAGING, INC Methods and apparatus for synthesizing imaging agents, and intermediates thereof
9056138, Mar 01 2002 Bracco Suisse SA; Dyax Corp. Multivalent constructs for therapeutic and diagnostic applications
9161997, Feb 13 2004 Bristol-Myers Squibb Pharma Company Contrast agents for myocardial perfusion imaging
9295737, Dec 09 2005 Bracco Suisse SA Targeting vector-phospholipid conjugates
9381258, Mar 01 2002 Bracco Suisse S.A. Targeting vector-phospholipid conjugates
9408926, Mar 01 2002 Bracco Suisse S.A. KDR and VEGF/KDR binding peptides and their use in diagnosis and therapy
9408927, Feb 29 2008 LANTHEUS MEDICAL IMAGING, INC Contrast agents for applications including perfusion imaging
9421166, Dec 19 2001 BGP Products Operations GmbH Pulmonary delivery of aminoglycoside
9439862, May 10 2000 Novartis AG Phospholipid-based powders for drug delivery
9446155, Mar 01 2002 Bracco Suisse SA; Dyax Corp. KDR and VEGF/KDR binding peptides and their use in diagnosis and therapy
9545457, Jan 14 1998 Lantheus Medical Imaging, Inc. Preparation of a lipid blend and a phospholipid suspension containing the lipid blend
9554993, Sep 29 1997 Novartis AG Pulmonary delivery particles comprising an active agent
9555138, Aug 10 2012 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
9603951, Feb 08 2010 Lantheus Medical Imaging, Inc. Methods and apparatus for synthesizing imaging agents, and intermediates thereof
9629934, Mar 01 2002 Takeda Pharmaceutical Company Limited KDR and VEGF/KDR binding peptides and their use in diagnosis and therapy
9687571, Apr 15 2009 The DuPont Merck Pharmaceutical Company Stabilization of radiopharmaceutical compositions using ascorbic acid
9713651, Aug 10 2012 LANTHEUS MEDICAL IMAGING, INC Compositions, methods, and systems for the synthesis and use of imaging agents
9718786, Feb 13 2004 Lantheus Medical Imaging, Inc. Contrast agents for myocardial perfusion imaging
9789210, Jul 06 2016 LANTHEUS MEDICAL IMAGING, INC Methods for making ultrasound contrast agents
9913919, Jul 06 2016 LANTHEUS MEDICAL IMAGING, INC Methods for making ultrasound contrast agents
9919064, Aug 10 2012 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
Patent Priority Assignee Title
3015128,
3293114,
3479811,
3488714,
3594326,
3615972,
3732172,
3945956, Jun 23 1975 CASCO NOBEL AB, P O BOX 11010, S-100 61 STOCKHOLM, SWEDEN Polymerization of styrene acrylonitrile expandable microspheres
3960583, May 02 1974 Philadelphia Quartz Company Method of preparing modified hollow, largely spherical particles by spray drying
4108806, Dec 06 1971 CASCO NOBEL AB, P O BOX 11010, S-100 61 STOCKHOLM, SWEDEN Thermoplastic expandable microsphere process and product
4138383, Nov 24 1975 California Institute of Technology Preparation of small bio-compatible microspheres
4179546, Aug 28 1972 CASCO NOBEL AB, P O BOX 11010, S-100 61 STOCKHOLM, SWEDEN Method for expanding microspheres and expandable composition
4224179, Aug 05 1977 Battelle Memorial Institute Process for the preparation of liposomes in aqueous solution
4276885, May 04 1979 Schering, AG Ultrasonic image enhancement
4420442, Apr 13 1981 PQ Corporation Manufacturing process for hollow microspheres
4421562, Apr 13 1980 PQ Corporation Manufacturing process for hollow microspheres
4466442, Oct 16 1981 Schering Aktiengesellschaft Carrier liquid solutions for the production of gas microbubbles, preparation thereof, and use thereof as contrast medium for ultrasonic diagnostics
4540629, Apr 08 1982 PQ Corporation Hollow microspheres with organosilicon-silicate walls
4549892, Sep 22 1982 PQ CORPORATION, EXECUTIVE MALL, A CORP OF PA Process for producing hollow, bilayered silicate microspheres
4657756, Nov 17 1980 Schering Aktiengesellschaft Microbubble precursors and apparatus for their production and use
4681119, Nov 17 1980 Schering Aktiengesellschaft Method of production and use of microbubble precursors
4789501, Nov 19 1984 CURATORS OF THE UNIVERSITY OF MISSOURI, THE Glass microspheres
4822534, Mar 11 1987 Method of producing microspheres
4898734, Feb 29 1988 Massachusetts Institute of Technology Polymer composite for controlled release or membrane formation
4900540, Jun 20 1983 Trustees of the University of Massachusetts Lipisomes containing gas for ultrasound detection
4927623, Jan 14 1986 PFC THERAPEUTICS, LLC Dissolution of gas in a fluorocarbon liquid
5019370, Jul 10 1989 University of Kentucky Research Foundation Biodegradable, low biological toxicity radiographic contrast medium and method of x-ray imaging
5078994, Apr 12 1990 Eastman Kodak Company Microgel drug delivery system
5088499, Dec 22 1989 LANTHEUS MEDICAL IMAGING, INC Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same
5149319, Sep 11 1990 CEREVAST THERAPEUTICS, INC Methods for providing localized therapeutic heat to biological tissues and fluids
5171755, Apr 29 1988 HEMAGEN PFC, 655 MONTGOMERY STREET, SUITE 1710, SAN FRANCISCO, CA 94111, A LIMITED PARTNERSHIP OF CA Emulsions of highly fluorinated organic compounds
5186922, Mar 15 1985 ENDOVASC LTD , INC Use of biodegradable microspheres labeled with imaging energy constrast materials
5195520, Nov 05 1986 SCHLIEF, REINHARD Ultrasonic manometry process in a fluid by means of microbubbles
5205290, Apr 05 1991 WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEE Low density microspheres and their use as contrast agents for computed tomography
5219538, Mar 03 1988 NOVAVAX, INC Gas and oxygen carrying lipid vesicles
5425366, Feb 05 1988 ACUSPHERE, INC Ultrasonic contrast agents for color Doppler imaging
GB1044680,
JP62286534,
JP6360943,
WO9115244,
WO9217213,
WO9217436,
WO9221382,
WO9317718,
/////////////////////
Executed onAssignorAssigneeConveyanceFrameReelDoc
May 24 1995ImaRx Pharmaceutical Corp.(assignment on the face of the patent)
Jul 10 1995UNGER, EVAN C IMARX PHARMACEUTICAL CORP ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS 0076860093 pdf
Apr 18 1996UNGER, EVAN C IMARX PHARMACEUTICAL CORP ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS 0079240606 pdf
Oct 07 1999IMARX PHARMACEUTICAL CORP DUPONT CONTRAST IMAGING INC MERGER CHANGE OF NAME0126530112 pdf
Oct 07 1999IMARX PHARMACEUTICAL CORP Dupont Pharmaceuticals CompanyCHANGE OF NAME SEE DOCUMENT FOR DETAILS 0115410215 pdf
Jan 16 2001IRMARX THERAPEUTICS, INC Silicon Valley BankSECURITY INTEREST SEE DOCUMENT FOR DETAILS 0114970505 pdf
Oct 02 2001DUPONT CONTRAST IMAGING INC BRISTOL-MYERS SQUIBB MEDICAL IMAGING, INC CHANGE OF NAME SEE DOCUMENT FOR DETAILS 0137740920 pdf
Jul 19 2004Silicon Valley BankIMARX THERAPEUTICS, INC RELEASE0155920901 pdf
May 17 2006ImaRx Pharmaceutical CorporationIMARX THERAPEUTICS, INC ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS 0176260618 pdf
Jan 08 2008BRISTOL-MYERS SQUIBB MEDICAL IMAGING, INC ABLECO FINANCE LLC, AS COLLATERAL AGENTGRANT OF SECURITY INTEREST0203710523 pdf
Feb 14 2008BRISTOL-MYERS SQUIBB MEDICAL IMAGING, INC LANTHEUS MEDICAL IMAGING, INC CHANGE OF NAME SEE DOCUMENT FOR DETAILS 0206090497 pdf
May 10 2010LANTHEUS MEDICAL IMAGING, INC HARRIS N A , AS COLLATERAL AGENTSECURITY AGREEMENT0243900733 pdf
May 10 2010ABLECO FINANCE LLCLANTHEUS MEDICAL IMAGING, INC RELEASE OF PATENT SECURITY AGREEMENT0243800363 pdf
Jul 03 2013BMO HARRIS BANK N A WELLS FARGO BANK, NATIONAL ASSOCIATION, AS ASSIGNEEASSIGNMENT OF SECURITY INTEREST IN PATENTS0307400335 pdf
Mar 30 2017Wells Fargo Bank, National AssociationLANTHEUS MI REAL ESTATE, LLCRELEASE OF SECURITY INTEREST IN CERTAIN PATENTS0421150715 pdf
Mar 30 2017Wells Fargo Bank, National AssociationLANTHEUS MEDICAL IMAGING, INC RELEASE OF SECURITY INTEREST IN CERTAIN PATENTS0421150715 pdf
Mar 30 2017Wells Fargo Bank, National AssociationLANTHEUS HOLDINGS, INC RELEASE OF SECURITY INTEREST IN CERTAIN PATENTS0421150715 pdf
Dec 02 2022MOLECULAR INSIGHT PHARMACEUTICALS, INC CITIZENS BANK, N A SECURITY INTEREST SEE DOCUMENT FOR DETAILS 0620470960 pdf
Dec 02 2022PROGENICS PHARMACEUTICALS, INC CITIZENS BANK, N A SECURITY INTEREST SEE DOCUMENT FOR DETAILS 0620470960 pdf
Dec 02 2022LANTHEUS MEDICAL IMAGING, INC CITIZENS BANK, N A SECURITY INTEREST SEE DOCUMENT FOR DETAILS 0620470960 pdf
Dec 02 2022PSMA Development Company, LLCCITIZENS BANK, N A SECURITY INTEREST SEE DOCUMENT FOR DETAILS 0620470960 pdf
Date Maintenance Fee Events
Jan 28 2000M183: Payment of Maintenance Fee, 4th Year, Large Entity.
Jan 12 2004M1552: Payment of Maintenance Fee, 8th Year, Large Entity.
Jan 25 2008M1553: Payment of Maintenance Fee, 12th Year, Large Entity.


Date Maintenance Schedule
Aug 20 19994 years fee payment window open
Feb 20 20006 months grace period start (w surcharge)
Aug 20 2000patent expiry (for year 4)
Aug 20 20022 years to revive unintentionally abandoned end. (for year 4)
Aug 20 20038 years fee payment window open
Feb 20 20046 months grace period start (w surcharge)
Aug 20 2004patent expiry (for year 8)
Aug 20 20062 years to revive unintentionally abandoned end. (for year 8)
Aug 20 200712 years fee payment window open
Feb 20 20086 months grace period start (w surcharge)
Aug 20 2008patent expiry (for year 12)
Aug 20 20102 years to revive unintentionally abandoned end. (for year 12)